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J. Biol. Chem., Vol. 282, Issue 29, 21327-21336, July 20, 2007

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Mitochondrial Reactive Oxygen Species Signal Hepatocyte Steatosis by Regulating the Phosphatidylinositol 3-Kinase Cell Survival Pathway^*

From the Department of Pediatrics, Children's Memorial Hospital, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614

Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H₂O₂, transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H₂O₂ is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H₂O₂ does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H₂O₂ activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.

Received for publication, February 28, 2007 , and in revised form, May 2, 2007.

^* This work was supported in part by the Children's Memorial Research Center, the American Association for the Study of Liver Diseases, the Children's Liver Research Fund of the Children's Memorial Foundation, and the Liver Foundation for Kids (Lemont, IL). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Children's Memorial Research Center, 2300 Children's Plaza, Chicago, IL 60614. Tel.: 773-880-4643; Fax: 773-975-8671; E-mail: p-whitington{at}northwestern.edu.

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